The global scale-up of antiretroviral therapy (ART) over the past decade represents one of the great public health and human rights achievements of recent times. Moving from an individualized treatment approach to a simplified and standardized public health approach has been critical to ART scale-up, simplifying both prescribing practices and supply chain management. In terms of the latter, the risk of stock-outs can be reduced and simplified prescribing practices support task shifting of care to nursing and other non-physician clinicians; this strategy is critical to increase access to ART care in settings where physicians are limited in number. In order to support such simplification, successive World Health Organization guidelines for ART in resource-limited settings have aimed to reduce the number of recommended options for first-line ART in such settings. Future drug and regimen choices for resource-limited settings will likely be guided by the same principles that have led to the recommendation of a single preferred regimen and will favour drugs that have the following characteristics: minimal risk of failure, efficacy and tolerability, robustness and forgiveness, no overlapping resistance in treatment sequencing, convenience, affordability, and compatibility with anti-TB and anti-hepatitis treatments.